Nortdptyline hydrochloride, available as a generic drug in the US for many years, has recently been shown to be efficacious in the treatment of nicotine addiction associated with cigarette smoking. It is a tricyclic anti-depressant that is believed to modulate noradrenergic neurotransmission. Currently, buproprion is the only non-nicotine therapy approved by the FDA, and is believed to have a similar mechanism, although these mechanisms are not completely understood. One putative explanation of moderately higher quit-rates observed for anti-depressive therapy is the following: smoking and depression are highly linked, and subsequent relief of depression, which may be especially acute just after smoking cessation target date, may facilitate continued abstinence. This notion has not been supported as strongly, however, where psychological interventions have been substituted as a relief for depression. This suggests there may exist an ill characterized molecular mechanism which may be providing more direct benefit for continued smoking cessation. On the other hand, even if the benefit is indirectly influenced through changes in mood states, it has been informally suggested that relief of anxiety, in addition to relief of depression, may play a similar role. Nortriptyline is a considerably less expensive alternative to buproprion, and affords comparable efficacy, although it does have a more problematic safety profile. Although generally non-addictive, nortriptyline, like all tricyclics, can have serious anticholinergic side effects, and an overdose is potentially lethal. It is unknown whether low doses of nortriptyline, which may be sub-therapeutic for relief of depression/anxiety, might yet be therapeutic for smoking cessation. The safety profile of lower doses, which might be expected to be more favorable than nominal recommended doses, has not been examined in the context of a smoking cessation study. Doses are typically titrated up to 50-150 mg/day, the maximum recommended dose. Previous studies have used titrated doses up to fixed target doses, typically 75 mg/day. In this pilot project, we are proposing a randomized, placebo-controlled, and double-blinded dose-response clinical trial of nortriptyline utilizing fixed target daily dose levels of 0 mg (placebo), 25 mg, 50 mg, and 75 mg. The specific aims are (1) to describe and determine the safety profile of nominal to low dose levels not usually prescribed; (2) to determine how relief of depression and anxiety is related to dose; and (3) to determine whether there is mere evidence of the existence of a molecular or other mechanism which works independently of mood states, that improves quit rates. If this research is successful, more thorough studies may be warranted. It could generate novel hypotheses and more enlightened directions for cessation research. More pragmatically, it might promote the use of nortriptyline under safer doses, and could remove insurance coverage barriers for smoking cessation therapy.